Phase I study to assess the pharmacokinetics and the effect on cardiac repolarization of amrubicin and amrubicinol in patients with advanced solid tumors

Purpose To evaluate the pharmacokinetics and cardiac repolarization effect (measured by QT/QTc interval) of amrubicin and its active metabolite amrubicinol in non-Japanese patients with advanced solid tumors. Methods Patients received amrubicin 40 mg/m 2 /day as a 5-min infusion on days 1–3 of a 21-day cycle. During cycle 1, serial blood and plasma samples were collected on days 1–9 and time-matched triplicate electrocardiograms on the “off-drug” visit (1–5 days prior to start of treatment) and days 1–9. Results Twenty-four patients were treated. Amrubicinol reached peak concentration 2–4 h after amrubicin administration and had a terminal half-life of 53 h. Distribution of amrubicinol into erythrocytes was fivefold greater than into plasma. The molar ratio of amrubicinol to amrubicin in blood was 0.67 on day 3. The presence of an NQO1 polymorphism did not alter drug exposure. The upper bound of the one-sided 95 % confidence interval for the time-matched, baseline-adjusted change from the off-drug day in QTcI (individual correction) was <10 ms at all times and was only >10 ms (10.20 ms) at a single time point for QTcF (Fridericia correction). No relationship was observed between blood amrubicin or amrubicinol concentrations and QTcF changes. All QTcF measurements were <480 ms, and none increased by >60 ms from baseline. Conclusions Data suggest that amrubicinol is an important active metabolite in humans and that both compounds were not associated with clinically relevant QTc interval prolongation at the dose regimen studied.